Chapter 1 Recent Advances in Corticotropin-Releasing Factor Receptor Antagonists

Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

“…The key intermediates 8c-d for the target compounds were prepared from the dialkylamino derivatives 4a-b by halogenation at the 4-position of the core using NBS and chlorination at the 2-position using POCl 3 . The 3-pentyl analog 8a was derived from a corresponding benzimidazol-2-one 3a by the reverse order of chlorination, that is, the first and second chlorinations were performed at the 2-and 4-positions of the core to give 6a and 8a, respectively.…”

“…1,2 CRF is believed to be the main regulator of the hypothalamus-pituitary-adrenocortical (HPA) axis via CRF 1 receptors. 3,4 After exposure to stress, secretion of CRF increases in the neurons of the paraventricular nucleus of the hypothalamus and stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. 5,6 In healthy individuals not suffering from life-threatening events, a negative feedback system against the activation of the HPA axis is operating; in contrast, the system collapses in patients with stress-related disorders.…”

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

“…Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide that mediates its actions through two G s -coupled G protein-coupled receptor subtypes, CRF 1 and CRF 2 . , CRF is believed to be the main regulator of the hypothalamus–pituitary–adrenocortical (HPA) axis via CRF 1 receptors and has an important role as a neurotransmitter in the mediation of stress-related behaviors. , After exposure to stress, secretion of CRF increases in the neurons of the paraventricular nucleus of the hypothalamus and stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. , ACTH subsequently induces the secretion of cortisol from adrenal glands. In a healthy individual, cortisol stimulates and controls the hypothalamic secretion of CRF, which indicates that a negative feedback system against the activation of the HPA axis is operating.…”

Predictive QSAR modeling of substituted Phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists: computational approach

“…It has been shown that intracerebroventricular injection of CRF in rats produces behavioral and physiological changes that mimic the effects of stress (Dunn and Berridge 1990). The potential that CRF1 receptor antagonists offer to provide a novel mechanism for the treatment of depression and anxiety has captured the attention of numerous research groups (Dzierba 2008;Tellew and Luo 2008). A number of CRF-1 receptor antagonists have been reported to have entered clinical trials for depression and anxiety-related disorders (Kehne and Cain 2010;Kehne and Maynard 2009;Dzierba et al 2008).…”

“…The potential that CRF1 receptor antagonists offer to provide a novel mechanism for the treatment of depression and anxiety has captured the attention of numerous research groups (Dzierba 2008;Tellew and Luo 2008). A number of CRF-1 receptor antagonists have been reported to have entered clinical trials for depression and anxiety-related disorders (Kehne and Cain 2010;Kehne and Maynard 2009;Dzierba et al 2008). In the computer-aided drug design methods, especially quantitative structure-activity relationship (QSAR) is a good and accepted method for this aim.…”